Post-herpetic neuralgia is the predominant morbidity associated with development of herpes-zoster, also known as shingles. The neuralgia typically lasts for from one to six months and is often excruciatingly painful.
Evidence has accrued in recent years which shows that herpes-zoster is caused by reactivation of latent varicella virus [Straus et al., Ann. Int. Med. (1988); 108, 221-237; Hyman et al., Lancet (1983) 2, 814-816; Gilden et al., Nature (1983) 306, 478-80; Croen et al., Proc. Natl. Acad. Sci. USA (1988); 85, 9773-9777; Mahalingham at al., New Eng. J. Med. (1990) 323, 627-631]. The initial varicella infection may have occurred as a result of infantile chickenpox or as a result of immunization with a live-attenuated varicella zoster virus vaccine to prevent chickenpox. In either case, the virus appears to remain in the infected individual's system long after chickenpox or vaccination. The locus of VZV latency appears to be neural cells within dorsal root ganglia.
Years after VZV has become latent, the virus reactivates by an as yet poorly understood mechanism. Nonetheless, the reactivation of VZV and its subsequent replication gives rise to herpes zoster. It is in the course of and subsequent to this reactivation of VZV that severe post-herpetic neuralgia develops.
Numerous reports in the literature have suggested that there may be a correlation between diminished immune competence and reactivation of herpes zoster from its latent state. Suggestions of the mechanism by which reactivation occurs include diminished cell-based immunity, such as reduction of the number of blood CD4.sup.+ receptor bearing T-lymphocytes, which are responsible for recognizing non-self antigens presented by MHC type II molecules following phagocytosis of VZV. Alternatively, the reduced levels of CD8.sup.+ T-lymphocytes, responsible for killing cells in which MHC type I molecules recognize and present non-self antigents, has also been suggested as a possible mechanism perimissive for VZV reactivation. Neumeyer et al., [N.E.J. Med. p. 1456, May 29, 1986) noted a drop in the ratio of CD4.sup.+ /CD8.sup.+ prior to zoster, and subsequent increase of the ratio upon termination of the clinical syndrome.
In one study, a varicella vaccine was adminsitered to elderly subjects in an attempt to boost their CMI responses to VZV. VZV immunization of these seropositive individuals was undertaken because of the previously described age-related decline in VZV-specific CMI [Miller A E., Neurology. (1980); 30, 582-587; Berger R, Florent G. Just M., Infect. Immun. (1981); 32, 24-27; Burke B L, Steele, R W, Beard O W., Arch. Intern. Med. (1982); 142, 291-293] and the possibility that the age-related reactivation of VZV (as herpes zoster) is a consequence of this decline. This live attenuated vaccine was well tolerated; no severe local or systemic reactions occurred and the mild reactions were not very common. Systemic spread of vaccine virus, as manifested by minimal skin rash, did occasionally occur (possibly in 6/245 injections). While this is of theoretical concern in elderly patients with documented reduction of specific cell-mediated immunity, the resulting lesions and symptoms proved to be of no clinical significance. This is consistent with anecdotal observations that seropositive grandparents are not infected after exposure to grandchildren with varicella.
The deficits in VZV-specific immunity in the elderly occur in the context of generally reduced CMI responses. These are detected in assays of delayed hypersensitivity skin responses [Goodwin J S, et al., Clin. Exp. Immunol. (1982); 48, 403-410] and in in vitro proliferative responses of T lymphocytes stimulated by mitogens [Hayward A R, et al., J. Clin. Immunol. (1987); 7, 174-178; Tice R R, et al., J. Exp. Med. (1979); 149, 1029-1041; Murasko D M, et al., Am. J. Med. (1986); 81, 612-618]. Most studies document normal T cell number, but there is a decrease in CD4.sup.+ cells [Nagel Je, et al., J. Immunol. (1981); 127, 2086-2088; Thompson J S, at al., J. Am. Geriate Soc. (1984); 32, 274-281]. Natural killer cell number and function are normal in these patients [Hayward A R, Herberger M., J. Clin. Immunol. (1987); 7, 174-178; Nagel Je, et al., J. Immunol. (1981); 127, 2086-2088]. An increased cell cycle time, as suggested in the study of Tice et al, would be a possible explanation for the loss of CMI with aging [Tice R R, et al., J. Exp. Med. (1979); 149, 1029-1041]. However, subsequent studies do not favor a change in cell cycle or any reduction in the degree of clonal expansion following antigen stimulation [Staiano-Coico L, et al., J. Immunol. (1984); 132, 1788-1792; Sohnie P G, et al., Clin. Exp. Immunol. (1982); 47, 138-146]. Instead, DNA analyses show an increased frequency of DNA damage, sister chromatid exchanges, and cell loss in mitrogen stimulated cells from the elderly [Dutkowski R T, et al., Mutat. Res. (1985); 149, 505-512]. Reduced proliferative responses to mitogens are not necessarily accompanied by reduced IL2 or IL2R synthesis [Dutkowski R T, et al., Mutat. Res. (1985); 149, 505-512]. The most consistent defect found by Chopra et al., was increased gamma-interferon production and a reduced survival of stimulated cells which supports the use of a booster [Chopra R K, et al., Clin. Immunol. Immunopathol. (1989); 53, 297-308].
Other studies in an aging population showed that the reduced VZV-specific immunity which accompanies the increased incidence of HZ in the elderly is at least partially explained by a reduced frequency of VZV-specific CD4.sup.+ cells in blood. However, these patients have normal T cell numbers and their NK cell activity is preserved in response to VZV antigen, providing that sufficient IL2 is present [Hayward A R, et al., J. Clin. Immunol. (1987); 7, 174-178]. The frequency of T cells expressing the memory cell phenotype (CD45RO) increases with age from a mean of 43+17% at 28 years to 65+14% at 70 years, so the decline in VZV-specific immunity with aging is not due to a selective loss of this subset. CD45RO.sup.+ cells make more .gamma.-interferon than CD45RA.sup.- cells, correlating with the results of Chopra and co-worker.
Whatever the mechanism of zoster control or reactivation, no medical evidence has effectively demonstrated prevention of herpes zoster reactivation (zoster), or diminution of post-herpetic neuralgia. Chemotherapeutic agents as a class have been dismal in adressing this painful condition [Watson, C. P. N., Neurol. Clin., 7, 231-248 (1989); Straus, et al., Ann. Int. Med. 108, 221-237 (1988)].
This invention is a method for reducing post-herpetic neuralgia and for ameliorating or abrogating herpes zoster reactivation. The efficacy of the method is demonstrated by positive results obtained in vivo in which the level of VZV specific lymphocytes increases. This increase in responder cell frequency, RCF, induced by immunization according to the method of this invention, yields an immune state in vivo which is refractory to the diseased state, including VZV reactivation and post herpetic neuralgia. Broad based, multicenter, long-term clinical investigation in which at-risk individuals are administered live-attenuated, killed, or subunit antigens, purified from VZV or from recombinant production shows that immunization according to this invention results in significant protection against VZV reactivation, or if reactivation occurs, significant reduction in the duration or severity of the post herpetic neuralgia.